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. 2021 Oct 21:12:720196.
doi: 10.3389/fphys.2021.720196. eCollection 2021.

Differential Regulation of the Asthmatic Phenotype by the Aryl Hydrocarbon Receptor

Hussein Traboulsi  1   2   3 , Angela Rico de Souza  1   2 , Benoit Allard  1 , Zahraa Haidar  1   2   3 , Mark Sorin  1   2   3 , Vanessa Moarbes  1   2   3 , Elizabeth D Fixman  1   2   3 , James G Martin  1   2   3 , David H Eidelman  1   2   3 , Carolyn J Baglole  1   2   3   4   5
Affiliations

Differential Regulation of the Asthmatic Phenotype by the Aryl Hydrocarbon Receptor

Hussein Traboulsi et al. Front Physiol. .

Abstract

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates the metabolism of xenobiotics. There is growing evidence that the AhR is implicated in physiological processes such proliferation, differentiation, and immune responses. Recently, a role of the AhR in regulating allergic asthma has been suggested, but whether the AhR also regulates other type of asthma, particularly occupational/irritant-induced asthma, remains unknown. Using AhR-deficient (Ahr-/- ) mice, we compared the function of the AhR in the response to ovalbumin (OVA; allergic asthma) vs. chlorine (Cl2; irritant-induced asthma) exposure. Lung inflammation and airway hyperresponsiveness were assessed 24h after exposure to Cl2 or OVA challenge in Ahr-/- and heterozygous (Ahr+/- ) mice. After OVA challenge, absence of AhR was associated with significantly enhanced eosinophilia and lymphocyte influx into the airways of Ahr-/- mice. There were also increased levels of interleukin-4 (IL-4) and IL-5 in the airways. However, OVA-induced airway hyperresponsiveness was not affected. In the irritant-induced asthma model caused by exposure to Cl2, the AhR did not regulate the inflammatory response. However, absence of AhR reduced Cl2-induced airway hyperresponsiveness. Collectively, these results support a differential role for the AhR in regulating asthma outcomes in response to diverse etiological agents.

Keywords: allergic asthma; aryl hydrocarbon receptor; chlorine; inflammation; lungs; neutrophils; occupational asthma.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Aryl hydrocarbon receptor (AhR) reduces ovalbumin (OVA)-induced airway inflammation. (A) Bronchoalveolar lavage (BAL) cells – presence of macrophages (arrowheads) in the BAL as the predominant cell type in PBS-exposed mice. There were more eosinophils (arrows) in the OVA-exposed Ahr−/− as well as Ahr+/− mice. (B) Total Cells – there was a significant increase in total cells in Ahr−/− mice exposed to OVA (**p =0.001 OVA compared with PBS; *p =0.0451 OVA-exposed Ahr−/− mice vs. OVA-exposed Ahr+/− mice). (C) Macrophages – there were no significant differences in macrophages numbers between the Ahr−/− and Ahr+/− exposed to OVA. (D) Eosinophils – there was a significant increase in eosinophils in OVA-exposed Ahr−/− mice compared with both PBS control (***p =0.0005) as well as OVA-exposed Ahr+/− mice (*p =0.0148). (E) Lymphocytes – the number of lymphocytes in OVA-exposed Ahr−/− mice was significantly higher than in OVA-exposed Ahr+/− mice compared with PBS control mice (**p =0.0016) as well as OVA-exposed Ahr+/− mice (*p =0.018). Results are expressed as the mean±SEM; values for individual mice from two independent experiments are shown.
Figure 2
Figure 2
Percentage of immune cells in OVA-induced airway inflammation. (A) Macrophages – there was a significant difference in the percentage of macrophages between OVA-challenged Ahr−/− and Ahr+/− mice (*p =0.0232; ****p =0.0001 between PBS and OVA-challenged Ahr−/− mice). (B) Eosinophils – there was a significantly higher percentage of eosinophils in OVA-exposed Ahr−/− mice compared with OVA-exposed Ahr+/− mice (**p =0.0011). (C) Lymphocytes – there was a significantly higher percentage of lymphocytes in OVA-exposed Ahr−/− mice compared with OVA-exposed Ahr+/− mice (**p =0.0016). Results are expressed as the mean±SEM from two independent experiments.
Figure 3
Figure 3
Aryl hydrocarbon receptor expression decreases the percentage of eosinophils in the lung parenchyma after exposure to OVA. (A) Gating Strategy – the gating strategy utilized for flow cytometry to quantify mature vs. activated eosinophils in lungs tissue is shown. The percentage of total (B), mature (C), and activated (D) eosinophils in lung tissue was significantly increased in Ahr−/− mice exposed to OVA compared with PBS control mice (**p =0.0028; 0.0088, and 0.0065, respectively). Results are expressed as the mean±SEM; values for individual mice are shown.
Figure 4
Figure 4
Ahr−/− mice exhibit increased levels of IL-4 and IL-5 following OVA challenge. Protein levels of interleukin-4 (IL-4), IL-5, and IL-13 were measured in the BAL fluid by multiplex assay. (A) IL-4 – there was a significant increase of IL-4 in the Ahr−/− mice exposed to OVA compared with the Ahr−/− mice exposed to PBS (**p =0.0095) and to the Ahr+/− mice exposed to OVA (*p =0.0466). (B) IL-5 – there was a significant increase of IL-5 only in the Ahr−/− mice exposed to OVA (*p =0.0396). (C) IL-13 – IL-13 was not significantly increased between any of the groups. Results are expressed as the mean±SEM; values for individual mice are shown.
Figure 5
Figure 5
Aryl hydrocarbon receptor does not influence lung function in the allergic asthma model. Lung mechanics were evaluated by flexiVent. There was no significant difference between OVA-immunized Ahr−/− and Ahr+/− mice in any of the parameters evaluated including resistance (A) and elastance (B). Results are expressed as the mean±SEM.
Figure 6
Figure 6
Aryl hydrocarbon receptor does not control chlorine (Cl2)-induced airway inflammation. Total and differential cell counts of the BAL of Ahr+/− and Ahr−/− was evaluated 24h after exposure to Cl2. There was a significant increase in total cells (A), total inflammatory cells (*p =0.0023; B), epithelial cells (*p =0.06001; C), macrophages **p =0.0039 (D) and neutrophils (*p =0.0297; **p =0.0055; E) and eosinophils (*p =0.0402; F) in mice exposed to Cl2 compared with the control mice. There was no significant difference (ns) between the Ahr+/− and Ahr−/− mice. Results are expressed as the mean±SEM; values for individual female mice are shown.
Figure 7
Figure 7
Aryl hydrocarbon receptor increases airway hyperresponsiveness after Cl2 exposure. Lung mechanics parameters included assessment of resistance (A) and elastance (B) by flexiVent in response to methacholine in Ahr+/− and Ahr−/− at 24h after exposure to air or Cl2. Cl2 increased resistance compared with the control. Respiratory resistance was significantly lower in Ahr−/− mice compared with Ahr+/− mice at the highest dose of methacholine (*p =0.0358). Results are expressed as the mean±SEM.
Figure 8
Figure 8
6-Formylindoleo [3,2-b] carbazole (FICZ) does not attenuate Cl2-induced airway inflammation. (A) BAL cells – there was an increase in neutrophils (open arrowheads) and epithelial cells (open arrows) 24h after exposure to Cl2. Macrophages are indicated as closed arrowheads. (B) Total Cells – there was a significant increase in total cells in mice exposed to Cl2 (****p =0.0001). FICZ had no effect on the total number of cells. (C) Macrophages – FICZ did not change macrophages in response to Cl2. (D) Neutrophils – there was a significant increase in neutrophils in response to Cl2 (*p =0.0313 and **p =0.001 in DMSO and FICZ treated mice, respectively). (E) Epithelial cells – there was a significant increase in BAL epithelial cells in mice treated with DMSO or FICZ and exposed to Cl2 (****p =0.0001). There was no significant difference between FICZ and DMSO-treated mice exposed to Cl2. Results are expressed as the mean±SEM; values for individual male mice are shown.
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